This work focuses on the effects of soil-structure interaction and the spatial variability of seismic motion due to site effects on the seismic response of a multi-span viaduct on pile foundations. In particular, site effects induced in a soft clay deposit by an inclined bedrock layout are evaluated through different models, characterised by an increasing level of accuracy, which allows determining the free-field motion that is adopted to perform soilstructure interaction analyses in the frame of the substructure approach. The seismic input is represented at the outcropping bedrock by a set of suitably selected and scaled real accelerograms. After a brief presentation of the adopted numerical procedure, analyses results are presented focusi...